Separately, acute pain and opioid administration have each been shown to induce a systemic pro-inflammatory response, theoretically putting the patient at risk for, or exacerbating, diseases of inflammation (i.e., heart disease, diabetes, arthritis). Surprisingly, unknown is the expression of these inflammatory responses when pain and opioid administration co-occur, as is the common clinical case of a patient with acute pain and taking opioid analgesics. An additive model would predict that pro-inflammatory processes are increased in the presence of both, yet better health outcomes for patients whose pain is adequately treated suggests otherwise. A patient population for whom the combined effects of pain and opioids on immune function are likely to be particularly complex are the estimated 5.2 million Americans aged 12 or older who abuse prescription opioids. Not only are these individuals at risk for poor pain management due to their status as an "addict", but there is good preclinical evidence to suggest that their chronic opioid use brings with it a general state of systemic inflammation, and thus setting the patient up for a unique or enhanced inflammatory response to the combination of acute opioids and pain. To effectively maximize health outcomes in this group of patients who self-administer prescription opioids in the absence of pain, clinicians need a more comprehensive understanding of the effects of their ongoing opioid use on inflammatory outcomes. To better understand the health implications of treating acute pain with opioids in general, and in patients who abuse prescription opioids in particular, inflammatory responses to the main and interaction effects of acute pain and opioid administration will be examined in well-characterized samples of each. Specifically, we will evaluate the inflammatory and cytokine responses to: (1) experimental (cold-pressor) pain;(2) an acute opioid (IV fentanyl 1mcg/kg) challenge;and (3) the combination of opioid administration (IV fentanyl 1mcg/kg) followed by cold-pressor pain, in healthy control subjects (n=22, 11 female) and age- and gender-matched prescription opioid abusers in buprenorphine treatment (n=22, 11 female). Markers of pro-inflammatory (IL-6, IL-12, TNF1) and anti-inflammatory (IL-4, IL-10) activity, as well as a nuclear transcription factor for pro- inflammatory cytokine expression ( NF-kb), will be followed over a 3hr time period to capture the duration of opioid analgesic activity, as well as second-messenger generated changes. The proposed study is unique in evaluating immune responses in the context of pain and opioid analgesia, innovative in the inclusion of inflammatory markers and relevant molecular signaling pathways, and noteworthy in including a vulnerable population of patients, prescription opioid abusers. This work will provide valuable and novel human data on how the inflammatory effects of acute pain, opioid administration, and chronic self-administration of opioids interact, and thus have clear clinical implications for the safe and effective management of pain with opioids. PUBLIC HEALTH RELEVANCE: Separately, acute pain and opioid administration each induce a systemic pro-inflammatory response, theoretically putting the patient at risk for, or exacerbating, inflammatory disease (i.e., heart disease, diabetes, arthritis). Yet, surprisingly, the inflammatory effects of these when they co-occur, such as in the common situation of the patient in pain and taking opioid analgesics, are essentially unknown. Further, the nature of this interaction in those individuals who abuse prescription opioids in the absence of pain has not been examined. In an effort to better understand the inflammatory effects of acute and chronic opioids in persons with and without pain, pro-inflammatory immune markers will be examined in healthy controls and treatment- seeking prescription opioid abusers.